Perfect adaptation achieved by transport limitations governs the inorganic phosphate response in S : cerevisiae

Cells cope with and adapt to ever-changing environmental conditions. Sophisticated regulatory networks allow cells to adjust to these fluctuating environments. One such archetypal system is the Saccharomyces cerevisiae Pho regulon. When external inorganic phosphate (P-i) concentration is low, the Pho regulon activates, expressing genes that scavenge external and internal Pi. However, the precise mechanism controlling this regulon remains elusive. We conducted a systems analysis of the Pho regulon on the single-cell level under well-controlled environmental conditions. This analysis identified a robust, perfectly adapted Pho regulon state in intermediate P-i conditions, and we identified an intermediate nuclear localization state of the transcriptional master regulator Pho4p. The existence of an intermediate nuclear Pho4p state unifies and resolves outstanding incongruities associated with the Pho regulon, explains the observed programmatic states of the Pho regulon, and improves our general understanding of how nature evolves and controls sophisticated gene regulatory networks. We further propose that robustness and perfect adaptation are not achieved through complex network-centric control but by simple transport biophysics. The ubiquity of multitransporter systems suggests that similar mechanisms could govern the function of other regulatory networks as well.

Automated summary

Cells have the ability to adapt to changing environmental conditions through regulatory networks. The Pho regulon in Saccharomyces cerevisiae is one such system that activates in low phosphate concentration to scavenge phosphate. However, the precise mechanism of this regulon was unclear until a systems analysis on single cells revealed an intermediate nuclear localization state of the transcriptional master regulator Pho4p. This finding explains the observed programmatic states of the regulon and improves our understanding of gene regulatory networks.